Researchers discover protein that causes sex bias in some diseases

Researchers have discovered the production of a protein that can protect against lupus and Sjogren’s syndrome in men, but heightens the propensity to schizophrenia.

The ground-breaking research solves the 50-year-old question why some diseases exhibit a sex bias, hitting harder or eliciting different symptoms in men or women.

The study, published in Natureby researchers at King’s, the Blavatnik Institute at Harvard Medical School and at the Broad Institute of MIT and Harvard, shows the greater abundance of an immune-related protein in men protects against lupus and Sjögren's but heightens vulnerability to schizophrenia.

Researchers measured protein levels in the cerebrospinal fluid of 589 people and blood plasma of 1,844 people. They found that samples from women aged 20 through 50 had significantly fewer complement proteins, called complement component 4 (C4) and produced by the C4 gene, than samples from men of the same age.

People with the most C4 genes were seven times less likely to develop systemic lupus erythematosus, an autoimmune condition that can range from mild to life-threatening, and 16 times less likely to develop primary Sjögren's syndrome, a systemic autoimmune syndrome, than those with the fewest C4 genes. On the other hand, those with the most C4 genes were 1.6 times more likely to develop the neuropsychiatric condition schizophrenia.

The genes produce more of the protein in men than in women.

Our study solves a 50-year puzzle in the genetics of the autoimmune disease, lupus (SLE). We show that too little of one immune protein, called complement C4 and too much of another set proteins, called HLA, increase the risk of getting lupus. SLE is much more common in women than men and in BAME groups. – Professor Tim Vyse, from the School of Life Course Sciences

He continued: “We showed how sex interacts with genetics to affect the amount of C4 protein. In addition, by studying SLE in people with African ancestry, we showed how ancestry, through genetics, affects immune function – it emphasises the value of being inclusive in the design of large-scale genetic studies.”

The findings will inform the ongoing development of drugs that modulate the complement system, which is part of the immune system. The study could also shed light on why BAME groups experience more severe symptoms of COVID-19.

Professor Vyse added: “Because SLE is more common and severe in BAME groups, there might be a relationship between SLE genetics and the genetics of COVID-19 infection, which shows a similar elevated severity in BAME groups. We have previously shown in SLE that this elevation in disease severity is due to genetic factors in non-EUROPEAN ancestry. More research is needed to understand the link between the two.”